Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin(POMC) -derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Review 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].
Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].
The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (a-helical CRF.sub.9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces "anxiolytic-like" effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].
DuPont Merck PCT application US 94/11050 describes corticotropin releasing factor antagonist compounds of the formula: ##STR2##
and their use to treat psychiatric disorders and neurological diseases. Included in the description are fused pyridines and pyrimidines of the formula: ##STR3##
where: Z is CR.sup.2 or N; A is CR.sup.30 or N; D is CR.sup.28 or N; and R.sup.3 can be aryloxy or arylthio.
Pfizer WO 95/33750 describes corticotropin releasing factor antagonist compounds useful in the treatment of CNS and stress disorders. The description includes compounds of the formulae: ##STR4##
where A is CR.sub.7 or N; B is OCHR.sub.1 R.sub.2 or SCHR.sub.1 R.sub.2 ; R.sub.1 is substituted or unsubstituted alkyl; R.sub.2 is substituted or unsubstituted alkyl, aryl or heteroaryl; R.sub.3 is methyl, halo, cyano, methoxy, etc.; R.sub.4 is H, substituted or unsubstituted alkyl, halo, amino, nitro, etc.; R.sub.5 is substituted or unsubstituted aryl or heteroaryl; R.sub.6 is H or substituted or unsubstituted alkyl; R.sub.7 is H, methyl, halo, cyano, etc.; R.sub.16 and R.sub.17 taken together form an oxo (.dbd.O) group; and G is .dbd.O, .dbd.S, .dbd.NH, .dbd.NCH.sub.3, hydrogen, methyl, methoxy, etc.
Pfizer WO 95/34563 describes corticotropin releasing factor antagonist compounds, including compounds of the formula: ##STR5##
where A, B and the R groups have definitions similar to those in WO 95/33750.
Pfizer WO 95/33727 describes corticotropin releasing factor antagonist compounds of the formula: ##STR6##
where A is CH.sub.2 and Z can be a heteroaryl moiety.
Ganguly et al., U.S. Pat. No. 4,076,711 describes triazolo[4,5-d]pyrimidines of the formula: ##STR7##
where X is halo, --NR.sub.1 R or alkoxy, with R1 and R each being H or alkyl; Y is alkyl, cycloalkyl, hydroxycycloalkyl, phenyl, bicycloalkyl or phenylalkyl or bicycloalkylalkyl; and Q is H or Y. The patent states that the compounds are useful in the treatment of psoriasis.
Tanji et al., Chem. Pharm. Bull. 39(11)3037-3040(1991), describes triazolo[4,5-d]pyrimidines of the formula: ##STR8##
where halo is I, Br or Cl, Ph is phenyl and Me is methyl. No utility for the compounds is described.
Settimo et al., Il Farmaco, Ed. Sc., 35 (4), 308-323 (1980) describes 8-azaadenines (triazolo[4,5-d] pyrimidines) of the formula: ##STR9##
where R1 is H or benzyl and R2 is p-methylphenyl.
Biagi et al., Il Farmaco, 49 (3), 183-186 (1994), describes N(6)-substituted 2-n-butyl-9-benzyl-8-azaadenines of the formula: ##STR10##
where R.sup.2 can be alkyl, phenyl, or benzyl. The paper states that the compounds have affinity for adenosine receptors.
Thompson et al., J. Med. Chem., 1991, 34, 2877-2882, describes N.sup.6,9-disubstituted adenines of the formula: ##STR11##
where Ph is phenyl or (when C-2 is unsubstituted) 2-fluorophenyl. The paper states that the compounds have selective affinity for the A.sub.1 adenosine receptor.
Kelley et al., J. Med. Chem. 1990, 31, 606-612, describes the compound ##STR12##
where R.sup.6 is NHC.sub.6 H.sub.5 and R.sup.9 is CH.sub.2 C.sub.6 H.sub.5, and reports that the compound was inactive when tested for anticonvulsant activity. The paper reports that various 6-(alkylamino)-9-benzyl-9H-purine analogs of the above compound exhibited anticonvulsant activity.
Kelley et al., J. Med. Chem. 1990, 33, 1360-1363, describes 6-anilino-9-benzyl-2-choro-9H-purines of the formula: ##STR13##
where Bz is benzyl or (when R.sup.4 is H) p-methylbenzyl and R.sup.4 is H or alkyl, alkoxy, halo, cyano, nitro, etc. Tests of the compounds for antirhinoviral activity are reported.
Kelley et al., J. Heterocyclic Chem., 28, 1099 (1991), describes 6-substituted-9-(3-formamidobenzyl)-9H-purines of the formula: ##STR14##
where R1 is NH2 or NHCHO. The compound where R1 is NHCHO was tested for benzodiazepine receptor binding and was inactive, although various analogs were active.
Khairy et al., J. Heterocyclic Chem., 22, 853 (1985), describes synthesis of certain 9-aryl-9H-purin-6-amines of the formula: ##STR15##
where the R groups are H, methyl, ethyl, isopropyl, chloro or fluoro.
Hoechst EP 298467 (1989) describes azapurine derivatives, including compounds of the structure: ##STR16##
where Q is O, S, SO, SO.sub.2 or NH.sub.2 ; X is O, S, SO or SO.sub.2 ; Z is H, halogen, CF.sub.3, 1-3C alkoxy or alkylthio; R.sup.2 is alkyl or alkoxy; R.sup.3 is OR.sup.2. These compounds are claimed to be useful for treating virus diseases, autoimmune diseases and cancers.
SS Pharmaceutical Co. Jp 59062595 (1984) and Jp 56131587 (1981) describe triazolopyrimidine derivatives, including compounds of the structure: where Q is O, S, SO.sub.2 ; R is amino or substituted amino, alkoxy, benzyloxy, halogen, or phenylhydrazino. These compounds are claimed to be useful as anticancer agents. ##STR17##
Fuji Jp 60194443 (1985) describe aza-indenes, including compounds of the structure: ##STR18##
where Q is O, S; R.sup.1, R.sup.2 and R.sup.3 are H, alkyl, aryl, aralkyl, amino, hydroxyl, alkoxy, carbamoyl, aryloxy, alkoxy carbonyl, cyano, halogen, alkylthio, arylthio, carboxyl, or mercapto, provided that at least one of the substituents is mercapto. These compounds are claimed to be useful as light-sensitizing agents, providing high photographic speed and contrast to silver halide emulsions.